There are various kinds of anticancer agents such as an alkylating agent, a platinum agent, an antimetabolite, an antitumor antibiotic, and an antitumor plant alkaloid. In addition, those anticancer agents exhibit the effects in some cases and exhibit no effect in other cases, which depends on the kind of cancer. However, it is known that, even if the cancer is a kind in which an anticancer agent is confirmed to be effective, the anticancer agent exhibits the effect in some cases and exhibits no effect in other cases, leading to interindividual differences. Whether an anticancer agent exhibits the effect on the cancer of an individual patient or not is designated to as sensitivity to the anticancer agent.
Irinotecan hydrochloride (CPT-11) is an anticancer agent developed in Japan, and has a mechanism of antitumor action based on the inhibition of topoisomerase I. In Japan, CPT-11 indicated for non-small-cell lung cancer, small cell lung cancer, cervical cancer, and ovarian cancer was approved as an effective drug in January 1994. Further, CPT-11 indicated for gastric cancer, colorectal cancer, breast cancer, squamous cell carcinoma, and malignant lymphoma was approved in July 1995. CPT-11 in multi-drug therapy has been recognized to be one of standard chemotherapy, in particular, as a first-line and a second-line for colorectal cancer all over the world, and CPT-11 had established the efficacy (Non-patent Documents 1 to 6).
In the chemotherapy for advanced or metastatic colorectal cancer, the combination of a key drug such as CPT-11 or oxaliplatin that launched in 1990's, and a fluoro-pyrimidine preparation as typified by fluorouracil (5-FU), which had been a main drug for a colorectal cancer therapy before the launches of the key drug, was used, whereby clinical performance including a survival rate has been improved dramatically. Nevertheless, it is the present situation the objective response rate is about 500, and the half of patient to which an anticancer agent was administered with high risks such as serious adverse events have not achieved the response. There is urgent need to establish a marker for predicting sensitivity to an anticancer agent for use in determining interindividual therapeutic response (responder/non-responder).
In general, the treatment schedule of cancer chemotherapy extends for a long period, and whether the objective response is achieved or not and whether the administration must be continued or not are determined after some courses of therapy were repeated monitoring for adverse events. However, it is the fact that along time has passed and a high health care cost has been charged until that time, and the adverse events have been also expressed. Therefore, if there is a means for predicting whether the effect can be obtained or not for individual patients in the earlier stage of the therapy, the burden of the patients and the expression of the adverse events can be alleviated, and the health care cost can be reduced.
CPT-11 itself has an antitumor activity and is activated by carboxyl esterase in a body to thereby be converted into 7-ethyl-10-hydroxycamptothecin (SN-38) having 100 to several thousands times stronger antitumor activity compared to that of CPT-11. It is thought that the coexistence of CPT-11 and SN-38 simultaneously in a body leads to the antitumor effect. SN-38 is glucuronidated by UDP-glucuronosyltransferase (UGT) in a liver cell and becomes an SN-38 glucuronate conjugate (SN-38G) having no cytotoxicity. Then, SN-38G is mainly excreted in the bile and transferred to the intestine, and thereafter, excreted in the stool. A part of SN-38G excreted in the intestine is subjected to metabolism and excretion while undergoing the following steps: SN-38G is deconjugated by β-glucuronidase of enteric bacteria, and becomes an active SN-38 again; and the active SN-38 is reabsorbed through a transporter in the intestinal epithelium, and is subjected to the enterohepatic circulation and glucuronate conjugation by UGT in an intestinal epithelial cell, and the like (Non-patent Document 7). In this case, SN-38 may damage intestinal mucosa and induce diarrhea. In addition, it is recognized that SN-38 influences bone marrow where active cell division occurs, to thereby induce erythrocytopenia, leukocytopenia, and thrombocytopenia.
It is demonstrated that the change in the exposure amount of SN-38 in a body caused by genetic polymorphism of UGT1A1 is one reason for the adverse effects such as serious diarrhea and neutropenia. However, because of the complexity disposition, for example, the conversion of CPT-11 as a prodrug into SN-38 as an active metabolite and detoxication thereof, the reproduction of SN-38 in the process of enterohepatic circulation, and the metabolism of CPT-11 itself and the production of SN-38 from the metabolite, there has been no report that the therapeutic effect can be predicted by pharmacokinetics. There is also reported that the expression level of the mRNA of carboxyesterase in a peripheral mononuclear cell is correlated with an AUC ratio of SN-38 and SN-38G but not correlated with a tumor reduction effect (Non-patent Document 8).
On the other hand, as a factor related with sensitivity or resistance to CPT-11, there is reported involvement of: the presence or absence of the mutation of topoisomerase I as a target of SN-38 and the expression level thereof; carboxylesterase activity involved in the conversion of CPT-11 into SN-38 (Non-patent Document 9); and a transporter (multidrug resistance protein (MRP)-1, MRP-2, or Breast cancer resistant protein (BCRP)/ABCG2) which influences the accumulation amount of CPT-11 or SN-38 in cells. In addition, a cell proliferation antigen Ki-67, a tumor suppressor gene p53, and the like are also studied on the correlation with the response to a therapy using CPT-11. In vitro, there has been most recently attempted to predict sensitivity to an anticancer agent systematically by combining the anticancer agent sensitivity data and the microarray data, and for camptothecin derivatives, topotecan has been studied (Non-patent Document 10). In clinical research, there has been recently reported that the plasma level of tissue inhibitor of metalloproteinase-1 (TIMP-1), the TIMP-1 having an anti-apoptosis action, is correlated significantly with the clinical prognosis of a therapy using CPT-11 and 5-FU in combination for metastatic colorectal cancer (Non-patent Document 11). Thus, the necessity of a biomarker for predicting sensitivity to CPT-11 is recognized and many researches have been carried out. However, there is reported that it has not been confirmed that both topoisomerase I as a target and thymidylate synthase as a factor for predicting sensitivity to 5-FU have a definite correlation with the therapeutic response to the therapy using 5-FU and CPT-11 in combination (Non-patent Document 12). No definite biomarker capable of predicting a therapeutic response has been established.